The influence of VKORC1 and CYP2C9 gene sequence variants on the stability of maintenance phase warfarin treatment

Abstract

Introduction: A substantial part of the inter-individual variation in vitamin K-antagonist dose can be explained by certain sequence variants in the genes CYP2C9 (NG-008385.1:g.8633C > T or*1/*2, NG-008385.1:g.47639A > C or*1/*3) and VKORC1 (NG-011564.1:g.6399C > T). Patients possessing these variant alleles require lower doses and have increased risk of overanticoagulation. Methods: We investigated the influence of the above sequence variants on stability of maintenance phase warfarin therapy in a prospective study of 300 consecutive patients followed for one year at an anticoagulant clinic. Results: Patients having one VKORC1 variant allele (n = 144) had a time in therapeutic range of INR (TTR) of 71.4%, significantly lower (p = 0.02) than the 76.7% TTR of patients with none (n = 96) or two (n = 46) variant alleles. Patients carrying the CYP2C9*3 allele (n = 40) trended towards lower TTR than patients without this variant allele (69.8% vs. 74.7%, p = 0.09). Six patients possessed two variant alleles of CYP2C9 (*2/*3 or*3/*3) and had significantly lower TTR (60.5% vs. 74.3%, p = 0.012) and higher risk of an INR > 4.5 (67% vs. 23%, p = 0.03) compared with the remaining patients. Conclusions: We observed modest effects of common gene sequence variants in CYP2C9 and VKORC1 on stability of maintenance phase warfarin therapy. Patients attending an anticoagulant clinic using computer-assisted dosage were safely monitored regardless of these sequence variants, but for the small subgroup of patients with the CYP2C9 genotype*2/*3 or*3/*3, treatment stability was reduced. © 2012 Elsevier Ltd. All rights reserved.